“Reserve” pool Competence maturation Fusion and collapse Coated-vesicle retrieval “Recycling” pool “Docked” “Primed” (?) (2) (2') (3') ? ? (1) (3) (4) (5) “Cocked” (?) Armed Fire! ? ? “Readily releasable” pool (RRP) Kiss... Run! Kiss-and-run fusion Phosphorylations, Ca++ fusion machine assembly ? ?? Ca++ •Fig. 6.6 Vesiclerecyclingpathways.Synapticvesicleshavebeenthoughttofusewiththemembranewhileemptyingtheircontentsandthenberecycledbyformingclathrin-coatedpitsthatareendocytosedtoformcoatedvesicles(1→ [2or2′]→ 3′→ 1).Analternativepathwaythatmayallowmorerapidrecyclingofvesicleshasbeenproposed.Thispathway,called“kissandrun,”involvesonlytransientfusionofthevesicletothepresynapticmembranetoformaporethroughwhichthevesiclecontentsmaybeemptied,followedbydetachmentofthevesiclefromthemembrane(1→ 2→ 3→ 4→ 5→ 1).(RedrawnfromValtortaF,MeldolesiJ,FesceR.Trends Cell Biol 2001;11:324.)
During synaptic transmission, vesicles must fuse with the plasma membrane to release their contents into the synaptic cleft. However, there must be a reverse process; otherwise, not only would it be hard to sustain the vesicle population, but the presynaptic membrane’s surface area would also grow with each bout of synaptic transmission, and its molecular content and functionality would likewise change (because, as just discussed, the protein content of the vesicle membrane is distinct from that of the terminal membrane).
There appear to be two distinct mechanisms by which vesicles are retrieved after release of their neurotransmitter content (Fig. 6.6 ). One mechanism is the endocytotic pathway commonly found in most cell types. Coated pits are formed in the plasma membrane, which then pinch off to form coated vesicles within the cytoplasm of the presynaptic terminal. These vesicles then lose their coat and undergo further transformations (i.e., acquire the correct complement of membrane proteins and be refilled with neurotransmitter) to become once again synaptic vesicles ready for release.
Evidence for a second, more rapid recycling mechanism has been obtained (see
Fig. 6.6 ). It involves transient fusion of the vesicle to the synaptic membrane and has been called “kiss and run.” In this case, fusion of the vesicle with the synaptic membrane leads to the formation of a pore through which the transmitter is expelled, but there is no wholesale collapse of the vesicle into the membrane. Instead, the duration of the fusion is very brief, after which the vesicle detaches from the plasma membrane and reseals itself. Thus, the vesicle membrane retains its molecular identity. Its contents can then simply be replenished, thereby making the vesicle ready for use again.
The relative importance of these two mechanisms is still being debated. However, at central synapses, which tend to be small and contain relatively few vesicles in comparison to the neuromuscular junction, the rapid time course of the kiss-and-run mechanism may help avoid the problem of vesicle depletion and the consequent failure of synaptic transmission during periods of high activity (many neurons in the CNS can show firing rates of several hundred hertz, and a few types of neuron can fire at rates of ≈ 1000 Hz).